Albumin-binding conjugates comprising a fatty acid and PEG

ABSTRACT

The present invention provides an albumin-binding compound essentially of the following elements: a spacer group, a water-soluble bridging group, a fatty acid chain and an acidic group characterised in that the acidic group is attached to the distal end of the fatty acid chain. The invention also provides an albumin-binding compound to which one or more biologically active moieties are attached.

The present invention relates to compounds capable of binding albuminfor use in extending the in vivo serum half-life of proteins or peptidesto which they are attached. More specifically the invention relates tomolecules comprising one or more biologically active moieties to whichone or more fatty acid chains capable of binding albumin are attached.Methods for the production of such molecules, and pharmaceuticalcompositions containing them, are also provided.

The use of fatty acids which bind albumin to increase in vivo half lifeof insulin was described by Kurtzhals et al., 1995, Biochem. J., 312,725-731. Insulin derivatives with affinity for albumin were produced byacylation of insulin with fatty acids.

The attachment of fatty acids to antibodies has been described inWO00/26256 and WO03/049684.

The present invention provides new compounds which are capable ofbinding albumin for use in extending the half-life of biologicallyactive moieties to which they are attached. Thus, the present inventionprovides albumin-binding compounds consisting essentially of thefollowing elements: a spacer group, a water-soluble bridging group, afatty acid chain and an acidic group. The compounds are characterised inthat the acidic group is attached to the distal end of the fatty acidchain. Each of the elements are as defined herein below. In one examplethe present invention provides albumin-binding compounds consistingessentially of:

In another example the present invention provides albumin-bindingcompounds consisting essentially of:

In a further example the present invention provides albumin-bindingcompounds consisting essentially of:

In a further example the present invention provides albumin-bindingcompounds consisting essentially of:

It will be appreciated by persons skilled in the art that each of thecomponent elements may be linked together using suitable linker groupsor bonds, including for example those described herein below.Also provided by the present invention are albumin-binding compoundsattached to one or more biologically active moieties. Therefore examplesof the present invention include compounds consisting essentially of:

Particular examples of the present invention are provided in formula(I), (II), (II) or (IV):

wherein:

Z, Z¹ and Z² independently represent the residue of a biologicallyactive moiety;

L, L¹ and L² independently represent a spacer group;

Y, Y¹ and Y² independently represent a covalent bond, —(CH₂)_(y)—,

B, B¹ and B² are independently absent or represent —CONH—, —NHCO—, —CO—,—OC(O)N(R²)—, —N(R²)C(O)O— or —NHCONH—;

V¹ and V² independently represent a covalent bond or —(CH₂)_(v)—;

X¹ and X² independently represent CR¹ or N;

M¹ represents a covalent bond or —(CH₂)_(m)—;

W¹ and W² independently represent a covalent bond or —(CH₂)_(w)—;

A¹ and A² independently represent —CONH—, —NHCO—, —CO—, —OC(O)N(R²)—,—N(R²)C(O)O— or —NHCONH—;

E, E¹ and E² independently represent a covalent bond or —(CH₂)_(e)—;

P, P¹ and P² independently represent a water-soluble bridging group;

T, T¹ and T² independently represent a covalent bond or a linker group;

F, F¹ and F² independently represent a fatty acid chain;

Q, Q¹ and Q² independently represent an acidic group;

R¹ represents hydrogen or C₁₋₄ alkyl;

R² represents hydrogen or C₁₋₄ alkyl;

e is 1, 2, 3 or 4;

v is 1, 2, 3 or 4;

w is 1, 2, 3 or 4;

y is 1, 2, 3, 4, 5 or 6; and

m is 1, 2 or 3.

As used herein, the term “C₁₋₄ alkyl” refers to straight-chained andbranched alkyl groups containing 1 to 4 carbon atoms. Such groups aremethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl andtert-butyl.

As used herein, the term “fatty acid chain” refers to the hydrocarbonbackbone of fatty acids (excluding the terminal acidic group) containing2 to 40 carbon atoms. Preferably the fatty acid chain for use in thepresent invention contains between 6 and 40 carbon atoms, morepreferably between 10 and 30 carbon atoms, even more preferably between15 and 25 carbon atoms. It will be appreciated that fatty acid chainlength may be selected on the basis of the intended use of the productand required circulating half-life. Fatty acids for use in the presentinvention may be saturated or may contain one or more units ofunsaturation. Suitable fatty acids for use in the present inventioninclude, for example, n-dodecanoate (C₁₂, laurate), n-tetradecanoate(C₁₄, myristate), n-hexadecanoate (C₁₆, palmitate), n-octadecanoate(C₁₈, stearate), n-eicosanoate (C₂₀, arachidate), n-docosanoate (C₂₂,behenate), n-tetracosanoate (C₂₄), n-triacontanoate (C₃₀),n-tetracontanoate (C₄₀), cis-Δ⁹-octadecanoate (C₁₈, oleate) and allcis-Δ^(5,8,11,14)-eicosatetraenoate (C₂₀, arachidonate).

Preferably the fatty acid chain for use in the present invention is astraight chain of between 14 and 24 carbon atoms. In one embodiment thefatty acid chain is a straight chain of 17 carbon atoms. In anotherembodiment the fatty acid chain is a straight chain of 23 carbon atoms.

As used herein, the term “residue” will be understood to mean thatportion of a biologically active moiety which remains after it hasundergone a substitution reaction as such terminology is familiar to theperson skilled in the art.

As used herein the term ‘water-soluble bridging group’ refers to anysubstantially water-soluble moiety familiar to the person skilled in theart which is capable of forming a bridge between the spacer group andthe fatty acid chain. In particular, the water-soluble bridging group,P, P¹ or P² will suitably comprise any substantially water-solublemoiety familiar to the person skilled in the art which is capable offorming a bridge between E, E¹ and E² and T, T¹ and T² respectively.

Examples of water-soluble bridging groups include water-soluble oligo-and poly-peptides comprising amino acids such as aspartic acid and/orglutamic acid; water-soluble mono-, di- and oligosaccharides such asglucose, glucosamine, lactose, sucrose or maltose; cyclodextrins; uronicacids; and branched or unbranched polysaccharides, e.g. a homo- orheteropolysaccharide such as amylose, dextran or glycogen.

Further examples of water-soluble bridging groups include any syntheticor naturally occurring substantially water-soluble, substantiallynon-antigenic polymer or copolymer, including, for example, optionallysubstituted straight or branched chain polyalkylene, polyalkenylene, orpolyoxyalkylene polymers or the polymerN-(2-hydroxypropyl)methacrylamide (HPMA). Particular optionalsubstituents which may be present on the above-mentioned syntheticpolymers include one or more hydroxy, methyl or methoxy groups.Particular examples of synthetic polymers include optionally substitutedstraight or branched chain poly(ethyleneglycol), poly(propyleneglycol),poly(vinylalcohol) or derivatives thereof, especially optionallysubstituted poly(ethyleneglycol).

Preferably the water-soluble bridging group for use in the presentinvention is a polymer, preferably a polyalkylene oxide such aspolyethylene glycol (PEG). As regards attaching PEG moieties in general,reference is made to “Poly(ethyleneglycol) Chemistry, Biotechnical andBiomedical Applications”, 1992, J. Milton Harris (ed), Plenum Press, NewYork; “Poly(ethyleneglycol) Chemistry and Biological Applications”,1997, J. Milton Harris and S. Zalipsky (eds), American Chemical Society,Washington D.C.; and “Bioconjugation Protein Coupling Techniques for theBiomedical Sciences”, 1998, M. Aslam and A. Dent, Grove Publishers, NewYork. Suitable molecular weight PEG molecules for use in the presentinvention range from 500 to 5,000. Particular PEG molecules includet-Boc-PEG-NHS, MW 3400; NHS-PEG-MAL, MW 3400; and NHS-PEG-MAL MW 2000(obtainable from Nektar, formerly Shearwater).

The water-soluble bridging group, P, P¹ and P² in the compounds offormula (I), (II), (III) and (IV) above will suitably be a substantiallywater-soluble, substantially non-antigenic polymer. Typical polymers ofwhich P, P¹ and P² are examples include polyalkylene oxides such aspolyethylene glycols (PEGs).

Preferably P, P¹ and P² are polymer moieties comprising the repeatingunit [OCH₂CH₂], where n is between 5 and 100. In one embodiment n isbetween 5 and 15, preferably either 5 or 12. In another embodiment n isbetween 40 and 100, preferably between 40 and 80. The repeating unitsmay be separated by one or more connecting groups, examples of whichinclude —CH₂CONH—, —CONHCH₂—, —(CH₂)₂NHCO—, —NHCO—, —NHCOCH₂—, —CONH—and —(CH₂)₂NHCONH—.

Suitably, P¹ and P² are identical.

The term ‘biologically active moiety’ as used herein refers to abiologically active compound having an available residue for attachmentto the compounds of the present invention. Biologically active compoundsfor use in the present invention are compounds suitable for medicinal ordiagnostic use in the treatment of animals, including humans.

Examples of biologically active moieties may include cytotoxins orcytotoxic agents including any agent that is detrimental to (e.g. kills)cells. Examples include taxol, cytochalasin B, gramicidin D, ethidiumbromide, emetine, mitomycin, etoposide, tenoposide, vincristine,vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracindione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone,glucocorticoids, procaine, tetracaine, lidocaine, propranolol, andpuromycin and analogs or homologs thereof.

Biologically active moieties also include, but are not limited to,antimetabolites (e.g. methotrexate, 6-mercaptopurine, 6-thioguanine,cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g.mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP)cisplatin), anthracyclines (e.g. daunorubicin (formerly daunomycin) anddoxorubicin), antibiotics (e.g. dactinomycin (formerly actinomycin),bleomycin, mithramycin, anthramycin (AMC), calicheamicins orduocarmycins), and anti-mitotic agents (e.g. vincristine andvinblastine).

Other biologically active moieties may include radionuclides such as¹¹¹In and ⁹⁰Y, Lu¹⁷⁷, Bismuth²¹³, Californium²⁵², Iridium¹⁹² andTungsten¹⁸⁸/Rhenium¹⁸⁸; or drugs such as but not limited to,alkylphosphocholines, topoisomerase I inhibitors, taxoids and suramin.

Other biologically active moieties include proteins, peptides andenzymes. Enzymes of interest include, but are not limited to,proteolytic enzymes, lyases, hydrolases, lyases, isomerases,transferases. Proteins, polypeptides and peptides of interest include,but are not limited to, immunoglobulins, toxins such as abrin, ricin A,pseudomonas exotoxin, or diphtheria toxin, a protein such as insulin,tumour necrosis factor, α-interferon, β-interferon, nerve growth factor,platelet derived growth factor or tissue plasminogen activator, athrombotic agent or an anti-angiogenic agent, e.g. angiostatin orendostatin, or, a biological response modifier such as a lymphokine,interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6),granulocyte macrophage colony stimulating factor (GM-CSF), granulocytecolony stimulating factor (G-CSF), nerve growth factor (NGF) or othergrowth factor and immunoglobulins.

Typical biologically active moieties of which Z¹, Z² and Z³ are residuesinclude antibodies and antibody fragments. Thus, the residues Z, Z¹ andZ² include residues of whole antibodies and functionally activefragments or derivatives thereof and may be, but are not limited to,polyclonal, monoclonal, multi-valent, multi-specific, humanized orchimeric antibodies, single chain antibodies, Fab fragments, Fab′ andF(ab′)₂ fragments and epitope-binding fragments of any of the above.

Antibodies include immunoglobulin molecules and immunologically activeportions of immunoglobulin molecules, i.e. molecules that contain anantigen binding site that specifically binds an antigen. Theimmunoglobulin molecules of the invention can be of any class (e.g. IgG,IgE, IgM, IgD or IgA) or subclass of immunoglobulin molecule.

Monoclonal antibodies may be prepared by any method known in the artsuch as the hybridoma technique (Kohler & Milstein, Nature, 1975, 256,495-497), the trioma technique, the human B-cell hybridoma technique(Kozbor et al., Immunology Today, 1983, 4, 72) and the EBV-hybridomatechnique (Cole et al., “Monoclonal Antibodies and Cancer Therapy”, pp.77-96, Alan R. Liss, Inc., 1985).

Antibodies for use in the invention may also be generated using singlelymphocyte antibody methods by cloning and expressing immunoglobulinvariable region cDNAs generated from single lymphocytes selected for theproduction of specific antibodies by, for example, the methods describedby Babcook, J. et al., Proc. Natl. Acad. Sci. USA, 1996, 93(15),7843-7848, WO 92/02551, WO2004/051268 and WO2004/106377.

Humanized antibodies are antibody molecules from non-human specieshaving one or more complementarity determining regions (CDRs) from thenon-human species and a framework region from a human immunoglobulinmolecule (see, for example, U.S. Pat. No. 5,585,089).

Chimeric antibodies are those antibodies encoded by immunoglobulin genesthat have been genetically engineered so that the light and heavy chaingenes are composed of immunoglobulin gene segments belonging todifferent species. These chimeric antibodies are likely to be lessantigenic. Bivalent antibodies may be made by methods known in the art(Milstein et al., Nature, 1983, 305, 537-539; WO 93/08829; Traunecker etal., EMBO J. 1991, 10, 3655-3659). Multi-valent antibodies may comprisemultiple specificities or may be monospecific (see, for example, WO92/22853).

The antibodies for use in the present invention can also be generatedusing various phage display methods known in the art and include thosedisclosed by Brinkman et al., J. Immunol. Methods, 1995, 182, 41-50;Ames et al., J. Immunol. Methods, 1995, 184, 177-186; Kettleborough etal. Eur. J. Immunol., 1994, 24, 952-958; Persic et al., Gene, 1997 187,9-18; and Burton et al., Advances in Immunology, 1994, 57, 191-280; WO90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO95/15982; and WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409;5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698;5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743; and 5,969,108.Techniques for the production of single chain antibodies, such as thosedescribed in U.S. Pat. No. 4,946,778, can also be adapted to producesingle chain antibodies. Also, transgenic mice, or other organisms,including other mammals, may be used to express humanized antibodies.

In one example the antibody fragments are Fab′ fragments which possess anative or a modified hinge region. A number of modified hinge regionshave already been described, for example, in U.S. Pat. No. 5,677,425,WO9915549, and WO9825971 and these are incorporated herein by reference.

Particular antibody fragments also include those described inWO2005003169, WO2005003170 and WO2005003171.

Where the biologically active moiety is an antibody, said antibody willin general be capable of selectively binding to an antigen. The antigenmay be any cell-associated antigen, for example a cell surface antigenon cells such as bacterial cells, yeast cells, T-cells, endothelialcells or tumour cells, or it may be a soluble antigen. Antigens may alsobe any medically relevant antigen such as those antigens upregulatedduring disease or infection, for example receptors and/or theircorresponding ligands. Particular examples of cell surface antigensinclude adhesion molecules, for example integrins such as P1 integrinse.g. VLA-4, E-selectin, P selectin or L-selectin, CD2, CD3, CD4, CD5,CD7, CD8, CD11a, CD11b, CD18, CD19, CD20, CD23, CD25, CD33, CD38, CD40,CD45, CDW52, CD69, carcinoembryonic antigen (CEA), human milk fatglobulin (HMFG1 and 2), MHC Class I and MHC Class II antigens, and VEGF,and where appropriate, receptors thereof. Soluble antigens includeinterleukins such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-12,IL-16 or IL-17, viral antigens for example respiratory syncytial virusor cytomegalovirus antigens, immunoglobulins, such as IgE, interferonssuch as interferon α, interferon β or interferon γ, tumour necrosisfactor-α, tumor necrosis factor-β, colony stimulating factors such asG-CSF or GM-CSF, and platelet derived growth factors such as PDGF-α, andPDGF-β and where appropriate receptors thereof.

Suitably, Z¹ and Z² are identical.

The spacer groups for use in the present invention, will suitablycomprise any moiety familiar to the person skilled in the art which iscapable of forming a bridge between the water-soluble bridging group andthe biologically active moiety. In particular the spacer groups L, L¹and L² will suitably comprise any moiety familiar to the person skilledin the art which is capable of forming a bridge between Y, Y¹ and Y² andthe residue Z, Z¹ and Z² respectively. For example, where Z, Z¹ or Z² isthe residue of an antibody or a fragment thereof containing a cysteineresidue the corresponding spacer group L, L¹ or L² will suitably be asuccinimide (i.e. the reaction product of a maleimide residue with thecysteine-containing polypeptide residue Z, Z¹ or Z² via a thiol linkage)linked to Y, Y¹ or Y² through its nitrogen atom.

Suitably, L¹ and L² are identical.

The presence of the distal acidic group enables the compounds of thepresent invention to bind albumin more effectively than compounds wherethe acidic group is absent altogether; or where the acidic group isincorporated into the framework of the molecule e.g. via an acyl(ester)or amide link, for instance where the fatty acid unit is facing the‘opposite’ direction leaving the lipid (hydrocarbon) chain of the fattyacid exposed. Examples of suitable acidic groups for use in the presentinvention include carboxylic, phosphonic, phosphinic, sulphinic andsulphonic acid groups

Q, Q¹ and Q² therefore represent an acidic group, preferably carboxyl,phosphonic, phosphinic, sulphinic or sulphonic acid groups.

In one embodiment, Q represents CO₂H.

In one embodiment, Q¹ represents CO₂H.

In one embodiment, Q² represents CO₂H.

Suitably Q¹ and Q² are identical.

The linker groups T, T¹ and T² will suitably comprise any moietyfamiliar to the person skilled in the art which is capable of forming abridge between the fatty acid chain F, F¹ and F² and the water-solublebridging group P, P¹ and P² respectively.

Typical examples of T, T¹ and T² include a covalent bond, —CONH—,—OCH₂CONH—, —OCONH— and —NHCO—.

In one embodiment, T represents —CONH—. In another embodiment, Trepresents —NHCO—. In another embodiment, T represents a covalent bond.

In another embodiment, T represents —OCH₂CONH—.

In one embodiment, T¹ represents —CONH—. In another embodiment, T¹represents —NHCO—. In another embodiment, T¹ represents a covalent bond.In a preferred embodiment, T¹ represents —OCONH—.

In one embodiment, T² represents —CONH—. In another embodiment, T²represents —NHCO—. In another embodiment T² represents a covalent bond.In a preferred embodiment, T² represents —OCONH—.

Suitably T¹ and T² are identical.

In one embodiment, X¹ represents CR¹. In another embodiment, Xrepresents N.

In one embodiment, X² represents CR¹. In another embodiment, Xrepresents N.

Suitably X¹ and X² are identical.

Suitably A¹ represents —CONH—, —NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O—or —NHCONH—. In one embodiment, A¹ represents —CONH—. In anotherembodiment, A¹ represents —NHCO—.

Suitably A² represents —CONH—, —NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O—or —NHCONH—. In one embodiment, A² represents —CONH—. In anotherembodiment, A² represents —NHCO—.

Suitably A¹ and A² are identical.

Suitably B represents —CONH—, —NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O—or —NHCONH. In one embodiment, B represents —CONH—. In anotherembodiment, B represents —NHCO—.

Suitably B¹ represents —CONH—, —NHCO—, —CO—, —OC(O)N(R²), —N(R²)C(O)O—or —NHCONH. In one embodiment, B¹ represents —CONH—. In anotherembodiment, B¹ represents —NHCO—. Where B¹ represents —CONH—, X¹typically represents CH.

Suitably B² represents —CONH—, —NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O—or —NHCONH. In one embodiment, B² represents —CONH—. In anotherembodiment, B² represents —NHCO—. Where B² represents —CONH—, X²typically represents CH.

Suitably B¹ and B² are identical.

In a preferred embodiment, V¹ represents a covalent bond. In anotherembodiment, V¹ represents —(CH₂)_(v)— in which v is as defined above.

In a preferred embodiment, V² represents a covalent bond. In anotherembodiment, V² represents —(CH₂)_(v)— in which v is as defined above.

Suitably, V¹ and V² are identical.

In one embodiment, W¹ represents a covalent bond. In another embodiment,W¹ represents —(CH₂)_(w)— in which w is as defined above.

In one embodiment, W² represents a covalent bond. In another embodiment,W² represents —(CH₂)_(w)— in which w is as defined above.

Suitably, W¹ and W² are identical.

Suitably, Y¹ and Y² are identical.

In one embodiment, M¹ represents a covalent bond. In another embodiment,M¹ represents —(CH₂)_(m)— in which m is as defined above.

In a preferred embodiment, R¹ is hydrogen. In another embodiment, R¹represents C₁₋₄alkyl, especially methyl.

In a preferred embodiment, R² is hydrogen. In another embodiment, R²represents C₁₋₄alkyl, especially methyl.

In one embodiment y is 2. In another embodiment, y is 4.

In one embodiment m is 1. In another embodiment, m is 2. In anadditional embodiment, m is 3. Favourably, m is 3.

In one embodiment e is 1. In another embodiment, e is 2. In anotherembodiment, e is 3.

In another aspect, the present invention provides novel compounds whichare valuable intermediates for the attachment of biologically activemoieties of which Z, Z¹ and Z² are residues. Thus, the invention alsoprovides compounds of formula (V), (VI), (VII) and (VIII):

wherein

L³, L⁴ and L⁵ represent groups capable of attaching the residue Z, Z¹and Z² respectively, or capable of being converted into such groups; and

each of the other variables is as defined above in relation to formula(I), (II), (III) or (IV).

Where Z, Z¹ or Z² is the residue of a polypeptide molecule (e.g. anantibody or a fragment thereof), the corresponding group L³, L⁴ or L⁵may be attached to the polypeptide through any available amino acidside-chain or terminal amino acid functional group located in theantibody fragment, for example any free amino, imino, thiol, hydroxy orcarboxyl group. Such amino acids may occur naturally in, for example,the antibody fragment or may be engineered into the fragment usingrecombinant DNA methods (see, for example, U.S. Pat. No. 5,677,425 andU.S. Pat. No. 5,219,996). In a preferred aspect of the invention the twogroups are covalently linked through a thiol group of a cysteine residuelocated in the antibody or fragment thereof, preferably in the hinge.The covalent linkage will generally be a disulphide bond or asulphur-carbon bond, preferably the latter. In one example where a thiolgroup is used as the point of attachment appropriately activated groups,for example thiol-selective derivatives such as maleimide and cysteinederivatives, may be used.

In a preferred feature, the groups L³, L⁴ and L⁵ are identical andrepresent maleimide derivatives attached to the remainder of themolecule through the maleimide nitrogen atom. In another feature, Q, Q¹and Q² are identical and represent CO₂H. Accordingly, one illustrativesubset of the compounds of formula (V), (VI), (VII) and (VIII) above isrepresented by the compounds of formula (IX), (X), (XI) and (XII):

Wherein Each of the Variables is as Defined Above.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I),(II), (III) or (IV) in association with one or more pharmaceuticallyacceptable carriers, excipients or diluents.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I), (II), (III) and (IV) may be formulated forparenteral administration by injection, e.g. by bolus injection orinfusion. Formulations for injection may be presented in unit dosageform, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.The compositions for injection may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising, preserving and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater, before use.

In addition to the formulations described above, the compounds offormula (I), (II), (III) and (IV) may also be formulated as a depotpreparation. Such long-acting formulations may be administered byimplantation or by intramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds according to the presentinvention may be conveniently formulated in a suitable ointmentcontaining the active component suspended or dissolved in one or morepharmaceutically acceptable carriers. Particular carriers include, forexample, mineral oil, liquid petroleum, propylene glycol,polyoxyethylene, polyoxypropylene, emulsifying wax and water.Alternatively, the compounds according to the present invention may beformulated in a suitable lotion containing the active componentsuspended or dissolved in one or more pharmaceutically acceptablecarriers. Particular carriers include, for example, mineral oil,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, benzyl alcohol, 2-octyldodecanol and water.

For ophthalmic administration the compounds according to the presentinvention may be conveniently formulated as microionized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds according to the presentinvention may be conveniently formulated as suppositories. These can beprepared by mixing the active component with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and so will melt in the rectum to release the activecomponent. Such materials include, for example, cocoa butter, beeswaxand polyethylene glycols.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular condition will vary depending on thecompound chosen and the condition of the patient to be treated. Ingeneral, however, daily dosages may range from around 10 ng/kg to 1000mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to40 mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50 mg/kg body weight for parenteral administration, and fromaround 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000mg, for nasal administration or administration by inhalation orinsufflation.

The compounds of the present invention may be prepared by using methodsanalogous to those in the Examples provided herein.

For example, the compounds of formula (I), (II), (III) and (IV) may beprepared by a process which comprises attachment of residue Z, Z¹ and Z²to a compound of formula (IX), (X), (XI) or (XII) respectively usingprocedures which are well known to the person skilled in the art.

The compounds of formula (V) wherein T is —CONH— may be prepared by aprocess which comprises reacting a compound of formula (XIII) with acompound of formula (XIV):

wherein J represents an activated carboxylate moiety; and the remainingvariables are as defined above.

Examples of activated carboxylate moieties for the substituent J includeacid chlorides; acid anhydrides; and the ester formed when a carboxylicacid (J=—CO₂H) is reacted with N-hydroxysuccinimide.

The reaction between compounds (XIII) and (XIV) is conveniently effectedin a suitable solvent, e.g. N,N-dimethylformamide, typically in thepresence of an organic base, e.g. triethylamine.

The compounds of formula (VI) wherein B¹ is —CONH— may be prepared by aprocess which comprises reacting a compound of formula (XV) with acompound of formula (XVI):

wherein J¹ represents an activated carboxylate moiety as defined abovefor J; and the remaining variables are as defined above.

The reaction between compounds (XV) and (XVI) is conveniently effectedin a suitable solvent, e.g. dichloromethane, typically in the presenceof an organic base e.g. triethylamine.

Where they are not commercially available, the compounds of formula(XIII), (XIV), (XV) and (XVI) may be prepared by methods analogous tothose described in the accompanying Examples, or by standard methodswell known from the art.

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as gel permeationchromatography; cation or anion exchange; preparative HPLC; or columnchromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999. The protecting groups may be removedat any convenient subsequent stage utilising methods known from the art.

The following non-limiting Examples illustrate the invention.

Intermediate 1

Fmoc-amino PEG12-propionic acid, MW 840 (150 mg) purchased from PolypureAS was dissolved in 1:4 piperidine:DMF (3 ml) and the solvent thenremoved after 10 min. The residue was dissolved in water (30 ml) andwashed with Et₂O (4×30 ml) and DCM (4×30 ml). The aqueous layer was thenacidified with 0.1M HCl and once again washed with DCM (3×30 ml). Thewater was removed, the residue dissolved in DCM, dried over MgSO₄ andthe solvent removed to give the desired compound as a colourlessoil/gum, 105 mg, 90%. In order to remove the final traces of piperidineand free up the amine, the HCl salt was dissolved in DCM (3 ml) and toit added 3 ml of dry triethylamine. The solvent was then removed and theprocedure repeated three more times to give the final product as apartial triethylamine salt.

m/z (LCMS ES+, 70V) 618.1 (MH+).

Intermediate 2

To Intermediate 1 (105 mg, 0.16 mmol) in DCM (6 ml) were added Et₃N (65mg, 0.64 mmol) and maleimido propionic acid NHS ester (64 mg, 0.24mmol). After 1 hour the solvent was removed, the residue dissolved in0.1M HCl (25 ml), washed with Et₂O (4×25 ml) and extracted into DCM(10×30 ml). The combined DCM fractions were reduced to 30 ml, extractedinto water (10×50 ml) and the water removed. The residue was dissolvedin DCM, dried over MgSO₄ and the solvent removed to give the product 94mg, 76% as a colourless oil/gum.

m/z (LCMS ES+, 70V) 769.0 (MH+).

δ_(H) (CDCl₃) 6.64 (2H, s), 6.59 (1H, br), 3.76 (2H, t, J7.1 Hz), 3.69(2H, t, J6.3 Hz), 3.57 (44H, br), 3.47 (2H, t, J4.9 Hz), 3.34 (2H, br),2.53 (2H, t, J6.3 Hz), 2.45 (2H, t, J7.1Hz).

Intermediate 3

To Intermediate 2 (94 mg, 0.12 mmol) in DCM (8 ml) were added NHS (21mg, 0.18 mmol) and EDC (35 mg, 0.18 mmol). After 4.5 hours the reactionwas diluted to 50 ml with DCM and washed with 0.1M HCl (3×30 ml). TheDCM was dried over MgSO₄ and the solvent removed to yield the NHS esteras a pale yellow, viscous oil 94 mg, 89%.

m/z (LCMS ES+, 70V) 866.1 (MH+).

δ_(H) (CDCl₃) 6.63 (2H, s), 6.58 (1H, br), 3.78 (4H, m), 3.57 (44H, m),3.46 (2H, t, J5.0Hz), 3.34 (2H, br), 2.83 (2H, t, J6.4Hz), 2.75 (4H, s),2.45 (2H, t, J7.2Hz).

Intermediate 4

A suspension of Intermediate 23 (22 mg, 0.075 mmol) and Et₃N (25 mg,0.25 mmol) in DMF (10 ml) was heated rapidly until a clear solution wasobtained. To the solution was then added t-Boc-PEG-NHS, MW3400 (206 mg,0.06 mmol) purchased from Shearwater and the solution allowed to cool.After 2 hours MP-Tosic acid resin (0.5 g, 1.43 mmol/g) was added andfiltered off after 1 hour. The solvent was removed, the residuedissolved in 0.1M HCl (30 ml) and washed with Et₂O (4×40 ml). Theaqueous solution was then extracted into DCM (4×40 ml), which was thenwashed with 0.1M HCl (3×30 ml), dried over MgSO₄ and the solvent removedto give the desired compound, 208 mg, 96% as a colourless waxy solid.

δ_(H) (CDCl₃) 4.87 (1H, br), 4.22 (2H, t), 3.81 (2H, t, J4.9Hz), 3.64(˜336H, brs), 3.54 (2H, t, J5.2Hz), 3.46 (2H, t, J4.9Hz), 3.31 (2H, t,J5.1Hz), 3.15 (2H, t, J6.8Hz), 2.32 (2H, t, J7.5Hz), 1.63 (2H, t), 1.48(2H, t), 1.44 (9H, s), 1.26 (26H, brs).

Intermediate 5

Method as for Intermediate 4, replacing Intermediate 23 withIntermediate 19. Yield 294 mg, 79%.

Intermediate 6

To a stirred solution/suspension of L-2-aminoadipic acid (460 mg, 2.85mmol) in methanol (75 ml) was added Et₃N (866 mg, 8.56 mmol) followed by(BOC) 20 (934 mg, 4.28 mmol). The reaction was left overnight with aclear solution being obtained after approximately 45 min. The solventwas removed, the residue dissolved in DCM, and the solvent removedagain. Addition and removal of DCM was repeated a further 5 times toensure complete removal of the methanol. The residue was then dissolvedin DCM (25 ml), to this added NHS (493 mg, 4.28 mmol) and EDC (821 mg,4.28 mmol) and the reaction left overnight. The solution was washed withwater (3×40 ml), dried over MgSO₄, and the solvent removed. The residuewas purified by silica column chromatography eluting with 50-75% EtOAcin Hexane to yield the desired compound as a colourless solid 256 mg,20%.

m/z (LCMS ES+, 70V) 478.1 (MNa+).

δ_(H) (CDCl₃) 4.97 (1H, br), 4.61 (1H, br), 2.74 (8H, s), 2.61 (2H, m),2.01 (1H, m), 1.85 (3H, m), 1.37 (9H, s).

Intermediate 7

Intermediate 4 (0.045 mmol) was dissolved in 9:1 TFA:DCM (3 ml) and thesolvent removed after 0.5 hours. The residue was dissolved in DCM (3 ml)and Et₃N (11 mg, 0.113 mmol) and Intermediate 6 (8.5 mg, 0.019 mmol)added and the reaction left for 3 days. The reaction was diluted to 20ml with DCM and PS-TsCl resin (0.5 g, 1.45 mmol/g) added. After 1.5hours the resin was filtered off, the filtrate washed with 0.1M HCl(3×30 ml), dried over MgSO₄ and the solvent removed to yield the desiredmaterial, 124 mg, 81%, as an off-white waxy solid.

m/z (LCMS ES−, 70V) for n=82, 2679 ((M-3H⁺)³⁻).

δ_(H) (CDCl₃) 6.88 (1H, t), 6.48 (1H, br), 5.30 (1H, m), 4.85 (2H, br),4.20 (4H, m), 4.08 (1H, m), 3.75-3.30 (˜650H, m), 3.08 (4H, m), 2.21(4H, t), 2.18 (2H, m), 1.80-1.50 (8H, brm), 1.43 (4H, m), 1.37 (9H, s),1.20 (52H, brs).

Intermediate 8

Method as for Intermediate 7 except Intermediate 5 is used in place ofIntermediate 4.

δ_(H) (CDCl₃) 6.89 (1H, t), 6.47 (1H, t), 5.35 (1H, d, J7.9Hz), 4.90(2H, br), 4.16 (4H, brm), 4.02 (1H, br), 3.80-3.30 (˜650H, brm), 3.09(4H, q, J6.8Hz), 2.24 (4H, t, J7.5Hz), 2.18 (2H, m), 1.80-1.50 (8H,brm), 1.43 (4H, m), 1.38 (9H, s), 1.20 (76H, br).

Intermediate 9

[4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butyl]-carbamic acid tert-butylester

Maleic anhydride (2.54 g, 26 mmol) and N-tBOC-1,4-diaminobutane (4.88 g,26 mmol) were heated under reflux overnight using a Dean-Stark trap. Thesolvent was removed to yield a gum/oil. The oil fraction dissolved inDCM and was loaded onto a silica column and eluted with 2:1 hexane:EtOActo afford the product, 1.85 g, 27% as a white solid.

m/z (ES+, 70V) 291.0 (MNa+), 169.0 (M-BOC.H+).

δ_(H) (CDCl₃) 6.62 (2H, s), 4.45 (1H, br), 3.47 (2H, t, J7.1Hz), 3.06(2H, q, J6.5Hz), 1.53 (4H, m), 1.37 (9H, s).

Intermediate 10

To a solution of NaH (60% in oil) (2.17 g, 0.054 mol) in THF (30 ml) andDCM (30 ml) at 0° C. was added over 15 min a solution of pentaethyleneglycol (5.17 g, 0.022 mol) in THF (10 ml). The reaction was stirred for1 hour at 0° C. and t-butyl bromoacetate (10.6 g, 0.054 mol) addedrapidly (˜10 sec.—CARE! effervescence). The reaction was maintained at0° C. for a further 1 hour then allowed to warm to ambient temperatureovernight. The reaction was filtered, the solvent was removed and theresidue purified by silica column chromatography eluting with DCMfollowed by EtOAc to elute the di-^(t)butyl ester. To this material wasadded THF (20 ml) and water (20 ml) and to the rapidly stirredbiphase/emulsion added LiOH (2 g). After 4 days the solution wasacidified to pH1 and the solvent removed. The soluble residues were thentaken up in DCM, dried over MgSO₄ and the solvent removed to yield thedi-acid as a pale oil ˜5 g.

m/z (LCMS ES+, 70V) 371.9 (MNH₄+).

Intermediate 11

Intermediate 10 (˜2 g) was dissolved in DMF (30 ml) and to it added EDC(4.9 g, ˜3 equiv.) and NHS (2.9 g, ˜3 equiv.). After overnight NHS esterformation the DMF was removed and the residue dissolved in DCM (100 ml).The DCM solution was washed with water (5×75 ml), dried over MgSO₄ andthe solvent removed to yield impure di-NHS ester. The residue waspurified by silica column chromatography eluting with EtOAc to yield theproduct as a colourless viscous oil/gum 970 mg.

m/z (LCMS ES+, 70V) 566.0 (MNH₄+).

δ_(H) (CDCl₃) 4.55 (4H, s), 3.81 (4H, m), 3.74 (4H, m), 3.68 (12H, s),2.87 (8H, s).

Intermediate 12

Intermediate 9 (98 mg, 0.36 mmol) was dissolved in 9:1 TFA:DCM (2 ml)and the solvent removed after 25 min. The residue was dissolved in DMF(1 ml) and added to a solution of Intermediate 11 (200 mg, 0.36 mmol)and Et₃N (184 mg, 1.8 mmol) in DCM (4 ml). NB May require more Et₃N toobtain a basic solution after TFA salt addition. After overnightreaction all the remaining NHS esters had hydrolysed to the acid. Thesolvent was removed, the residue dissolved in 0.1M HCl (30 ml) andextracted into DCM (3×30 ml), leaving the di-acid behind. The DCMsolution containing the desired material and the di-maleimide wasrapidly passed through 1″ of silica eluting with 10% methanol in DCM toremove the di-maleimide, followed by MeOH to elute the product, 29 mg.NB The methanol must be removed within a few minutes to avoid itreacting with the maleimide-pink solution!

m/z (LCMS ES+, 70V) 505.0 (MH+).

δ_(H) (CDCl₃) 7.06 (1H, brt), 6.63 (2H, s), 3.90 (2H, s), 3.86 (2H,brs), 3.58 (20H, br), 3.46 (2H, t, J7.0Hz), 3.22 (2H, q, J6.7Hz), 1.55(2H, m), 1.46 (2H, m).

Intermediate 13

Intermediate 12 (29 mg, 0.058 mmol) was dissolved in DCM (4 ml) and tothe solution added NHS (9.9 mg, 0.086 mmol) followed by EDC (16.5 mg,0.086 mmol). The reaction was left at ambient temperature overnight, thereaction diluted to 40 ml with DCM and the solution washed with 0.1M HCl(4×30 ml). The DCM fraction was dried over MgSO₄ and the solvent removedto afford the NHS ester as a colourless gum (30 mg). This was usedimmediately in the preparation of Example 8.

m/z (LCMS ES+, 70V) 602.0 (N4H+)

Intermediate 14

12-Aminododecanol hydrochloride

NH₂(CH₂)₁₁CH₂OH.HCl

12-Aminododecanoic acid (21.52 g, 100 mmol) was suspended in 100 cm³ THFand borane THF complex (500 mmol, 1M solution) added. The reaction wasleft overnight and carefully quenched with methanol before evaporationto small bulk. The residue was suspended in 1M HCl (500 ml) and heatedat 40° C. for 1 hr and left overnight. The white solid was filtered offand washed with cold 1M HCl. The product was recrystallised from 1M HCl,filtered off & dried over P₂O₅ in vacuo. Yield 18.70 g (79%). Mp 120° C.softens, 169° C. liquid.

C₁₂H₂₈NOCl⅕ H₂O requires C: 59.70%, H: 11.86%, N: 5.80%. Found: C:59.65%, H: 11.82%, N: 5.76%. m/z (ES+, 70V) 202.1 (MH+).

δ_(H) (CD₃CO₂D) 3.64 (2H, t), 3.06 (2H, t), 1.73 (2H, m), 1.57 (2H, m),1.2-1.5 (16H, m).

Intermediate 15

12-(Dibenzylamino)dodecanol

Bn₂N(CH₂)₁₁CH₂OH

Intermediate 14 (15 g, 63.2 mmol) was suspended in a mixture ofdichloromethane (150 ml) & saturated sodium carbonate in water (150 ml).Benzyl bromide (189.6 mmol, 33.7 g, 23.5 ml) was added slowly. Thesuspension cleared and reaction was complete after 4 hr. Aqueous ammonia(0.880, 30 ml) was added & the reaction left overnight. The organiclayer was dried (magnesium sulphate) & evaporated to dryness. Theresidues were dissolved with vigorous stirring in refluxing hexane. Theflask was left at −20° C. when crystals slowly appear. The crystals (Mp45° C.) were filtered off, (18.03 g, 75%).

C₂₆H₃₉N₁O₁ requires C: 81.84%, H: 10.30%, N: 3.67%. Found: C: 81.64%, H:10.24%, N: 3.54%. C₂₆H₃₉N₁O₁ requires 381. m/z (ES+, 70V) 382 (MH+).

δ_(H) (CDCl₃) 7.1-7.6 (10H, m), 3.64 (2H, t), 3.56 (4H, s), 2.41 (2H,t), 1.1-1.8 (22H, m).

Intermediate 16

12-(Dibenzylamino)dodecanal

Bn₂N(CH₂)₁₁CHOTo a solution of anhydrous dimethylsulphoxide (30 mmol, 2.13 ml) indichloromethane (200 ml) at −78° C. was added carefully oxalyl chloride(2.6 ml, 30 mmol) in dichloromethane (60 ml). After 15 mins Intermediate15 (10 g, 26 mmol) was added in dichloromethane (60 ml) and the reactionstirred for 20 mins at −78° C. Triethylamine (28 ml) was added dropwiseto the cold reaction. A precipitate formed and after 15 mins thereaction was allowed to reach room temperature. Water (100 ml) was addedto the reaction which was extracted with dichloromethane. The organiclayers were washed with water, dried (magnesium sulphate) & evaporatedto dryness. The residue was chromatographed (SiO₂, hexane −10% ethylacetate in hexane) to give the product as an oil (7.97 g, 80%). Thiscompound is unstable and should be used on the day of preparation.

I.R. 1725 cm⁻¹ (COH). C₂₆H₃₇NO requires 379.29. m/z (ES+, 70V) 380.3(MH+).

δ_(H) (CDCl₃) 1.32 (14H, br), 1.61 (4H: 2×p), 2.43 (2H, t), 2.44 (2H,t), 3.60 (4H, s), 7.2-7.5 (10H, m), 9.78 (1H, t). δ_(C) (CDCl₃) 22.0,26.9, 27.1, 29.0, 29.3, 29.4, 29.5 (9C), 43.8 (1C), 53.3 (1C), 58.2(2C), 126.6 (2C), 128.0 (4C), 128.6 (4C), 140.0 (2C), 202.3 (1C).

Intermediate 17

11-(Carboxyundecyl)triphenylphosphonium bromide

Ph₃P+(CH₂)₁₁CO₂H.Br−

To 12-bromododecanoic acid (3.000 g, 10.7 mmol) suspended inacetonitrile (12 ml) was slowly added triphenylphosphine (2.818 g, 10.7mmol). The reaction was heated at 100° C. (no condenser) with argonblowing over the flask until the reaction was a fusion, then maintainedat 100° C. (with condenser) for 24 hrs. The warm residues were dissolvedin acetonitrile (18 ml) and added dropwise to rapidly stirred cold (dryice) diethyl ether. The white precipitate of phosphonium salt formed wasthen filtered off and the dried (5.353 g, 92%).

Mp 110-112° C. C₃₀H₃₈O₂PBr requires C: 66.54%, H: 7.07%. Found: C:66.42%, H: 7.10%.

δ_(p) (CDCl₃) 24.3 (s). δ_(H) (CDCl₃) 1.05-1.30 (12H, br), 1.53 (6H,br), 2.28 (2H, t), 3.55 (2H, br), 7.6-7.8 (15H, m). δ_(C) (CDCl₃) 22.1,22.3, 22.8, 24.5, 28.8, 28.9, 30.0, 30.2 (10C), 34.2 (1 C), 117.3, 118.7(3 C), 130.3, 130.5 (6C), 133.3, 133.5 (6C), 134.9 (3C), 177.4 (1C).

Intermediate 18

24-(Dibenzylamino)-12-tetracosenoic acid

Bn₂N(CH₂)₁₁CH═CH(CH₂)₁₀CO₂HIntermediate 17 (13.52 g, 25 mmol) was dissolved in dry DMSO (or THF)(40 ml) under argon at ˜0° C. (no DMSO solidification). 2.2 equivalentsof 2.0M LDA. (25 ml) was added, the solution turning orange. Thereaction was left at 0° C. for ½ hour, and to the now dark orangesolution was added a solution of Intermediate 16 (7.97 g, 21 mmol) indry THF (30 ml). The solution was maintained at 0° C. for 4 hours thenadded to 2M HCl (50 ml). The aqueous layer was extracted withdichloromethane, the fractions combined, dried (MgSO₄) and the solventremoved to yield the crude material as a pale yellow gum. Silica columnchromatography (30-100% ethyl acetate in hexane) yielded the desiredproduct (6.20 g, 53%), as a pale yellow gum.

m/z (ES+, 70V) 562.5 (MH+), (ES−, 70V) 560.5 (M-H⁺)⁻.

δ_(H) (CDCl₃) 1.26 (30H, br), 1.42-1.72 (4H, m), 2.02 (4H, dxt), 2.34(2H, t), 2.46 (2H, t), 3.65 (4H, s), 5.36 (2H, t), 7.2-7.4 (10H, m).δ_(C) (CDCl₃) 25.0, 26.4, 27.2, 29.3, 29.6 (19C), 34.5 (1C), 52.9 (1C),57.7 (2C), 127.0 (2C), 128.2 (4C), 129.1 (4C), 129.9 (2C), 138.6 (2C),179.2 (1C).

Intermediate 19

24-Aminotetracosanoic acid

NH₂(CH₂)₂₃CO₂HIntermediate 18 (6.2 g) under an atmosphere of hydrogen was heated at60° C. overnight in glacial acetic acid using Pearlman's catalyst (10%w/w). The reaction was filtered through glass fiber & evaporated todryness. The product was crystallised from acetic acid/ether (4.2 g,100%). The product was subjected to high vacuum to remove traces ofacetic acid.

Mp 151-155° C. C₂₄H₄₉NO₂. 0.75 CH₃CO₂H requires C: 71.44%, H: 12.23%, N:3.27%. Found: C: 71.43%, H: 12.15%, N: 3.26%. m/z (ES+, 70V) 384.3(MH+).

δ^(H) (CD₃OD+TFA) 1.32 (38H, br), 1.65 (4H, br), 2.33 (2H, t), 2.74 (2H,m). δ_(C) (CD₃OD+TFA) partial 33.8 (1C), 35.3 (1C).

Intermediate 20

6-(Dibenzylamino)-1-hexanol

Bn₂N(CH₂)₅CH₂OHBenzyl bromide (61 ml, 511 mmol) was added to a stirred solution of6-amino-1-hexanol (20 g, 170 mmol) and triethylamine (142 ml, 1.02 mol)in acetonitrile (500 ml) at room temperature for two days. Theacetonitrile solution was concentrated to 100 ml and diluted with water.The aqueous phase was extracted with ethyl acetate, washed with brine,dried (magnesium sulphate) & evaporated to dryness to yield an orangeoil. The product was chromatographed on silica (hexane—50% ethylacetate/hexane) to yield a colourless oil (25 g, 50%).

δ^(H) (CDCl₃) 7.23-7.39 (10H, m), 3.59 (6H, m), 2.42 (2H, t), 1.47-1.56(4H, m), 1.24-1.32 (4H, m).

Intermediate 21

6-(Dibenzylamino)hexanal

Bn₂N(CH₂)₅CHO

To a stirred solution of DMSO (20 mmol, 1.41 ml) in dichloromethane (100ml) at −78° C. was carefully added oxalyl chloride (1.7 ml, 20 mmol) indichloromethane (30 ml). After 15 mins Intermediate 20 (5 g, 16.83 mmol)was added in dichloromethane (30 ml) maintaining the temperature at −78°C. The reaction was stirred for 20 mins and triethylamine (14 ml) addeddropwise. A precipitate formed, after 15 mins the reaction was allowedto reach room temperature. Water (100 ml) was added to the reactionwhich was extracted with dichloromethane. The organic layers were washedwith water, dried (magnesium sulphate) & evaporated to dryness. Theresidue was chromatographed (SiO₂, hexane −20% ethyl acetate in hexane)to give the product as an oil (4.10 g, 83%). C₂₀H₂₅NO requires C:81.31%, H: 8.53%, N: 4.74%. Found: C: 81.00%, H: 8.49%, N: 4.63%. m/z(ES+, 70V) 296 (MH+).

δ^(H) (CDCl₃) 9.71 (1H, s), 7.2-7.5 (10H, m), 3.57 (4H, s), 2.3-2.5 (4H,dt), 1.2-1.7 (6H, dm).

Intermediate 22

18-(Dibenzylamino)-12-octadecenoic acid

Bn₂N(CH₂)₅CH═CH(CH₂)₁₀CO₂HIntermediate 17 (1.082 g, 2 mmol) was dissolved in dry DMSO (5 cm³)under argon at ˜0° C. (no DMSO solidification). 2.2 equivalents of 2.0MLDA (4 ml) was added, the solution turning orange. The reaction was leftat 0° C. for ½ hour, and to the now dark orange solution was added asolution of Intermediate 21 (0.7 g, 2 mmol) in dry THF (10 ml). Thesolution was maintained at 0° C. for 4 hours then added to 2M HCl (50ml). The aqueous layer was extracted with ethyl acetate, the fractionscombined, dried (MgSO₄) and the solvent removed to yield the crudematerial as a pale yellow gum. Silica column chromatography (30% ethylacetate in hexane or 5% methanol in dichloromethane) yielded the desiredproduct (453 mg, 53%), as a low melting (Mp 21° C.) white solid.

C₃₂H₄₇NO₂ requires C: 80.45%, H: 9.92%, N: 2.93%. Found: C: 80.20%, H:9.92%, N: 2.74%. C₃₈H₅₉NO₂ requires 477. Found m/z (ES+, 70V) 478 (MH+).

δ_(H) (CDCl₃) 8.6-9.2 (1H, vbr), 7.39-7.21 (10H, m), 5.37-5.29 (2H, m),3.63 (4H, s), 2.48-2.43 (2H, t), 2.36-2.31 (2H, t), 2.01-1.97 (2H, t),1.66-1.55 (4H, m), 1.29-1.24 (18H, m).

Intermediate 23

18-Aminooctadecanoic acid

NH₂(CH₂)₁₇CO₂H

Intermediate 22 (13 g) under an atmosphere of hydrogen was heated at 60°C. overnight in glacial acetic acid with Pearlman's catalyst (10% w/w).The reaction was filtered hot through glass fibre & evaporated todryness. The product was crystallised from acetic acid/ether (8.2 g,100%). The product was subjected to high vacuum to remove traces ofacetic acid.

Mp 162-163° C. C₂₄H₄₉NO₂. 0.25H₂O requires C: 71.12%, H: 12.43%, N:4.61%.

Found: C: 71.20%, H: 12.35%, N: 4.49%. m/z (ES+, 70V) 300 (MH+).

δ_(H) (CD₃CO₂D) 3.06 (2H, t), 2.38 (2H, t), 1.63-1.73 (4H, m), 1.33(26H, m).

Intermediate 24

To a solution of Intermediate 3 (99 mg, 0.115 mmol) in DCM (3 ml) wereadded Et₃N (46 mg, 0.458 mmol) and Intermediate 1 (0.143 mmol). After 2hours MP-Tosic acid (1 g, 1.43 mmol/g) was added, stirred for 1 hour andremoved by filtration. The solvent was removed, the residue dissolved in0.1M HCl (20 ml), washed with diethyl ether (5×30 ml) and extracted intoDCM (10×20 ml). The DCM fractions were combined, washed with 0.1M HCl(20 ml), dried over MgSO₄ and the solvent removed to yield the product120 mg, 77% as a pale yellow oil.

m/z (ES+, 70V) 685 (MH₂ ²⁺).

δ_(H) (CDCl₃) 6.75 (1H, brt), 6.70 (2H, s), 6.33 (1H, brt), 3.76 (2H, t,J7.3Hz), 3.68 (4H, m), 3.57 (88H, m), 3.47 (4H, m), 3.34 (4H, m), 2.53(2H, t, J6.4Hz), 2.45 (2H, t, J7.3Hz), 2.41 (2H, t, J6.0Hz).

Intermediate 25

To a solution of Intermediate 24 (109 mg, 0.080 mmol) in DCM (4 ml) wereadded NHS (14 mg, 0.120 mmol) followed by EDC (23 mg, 0.120 mmol). Afterovernight reaction the solution was diluted with DCM to 40 ml, washedwith 0.1M HCl (5×30 ml), dried over MgSO₄ and the solvent removed togive the product 103 mg, 88% as a colourless oil/gum.

m/z (ES+, 70V) 733 (MH₂ ²⁺).

δ_(H) (CDCl₃) 6.63 (2H, s), 6.62 (1H, brt), 6.37 (1H, brt), 3.78 (4H,m), 3.67 (2H, t, J6.0Hz), 3.56 (88H, br), 3.46 (4H, m), 3.35 (4H, m),2.83 (2H, t, J6.5Hz), 2.77 (4H, s), 2.44 (2H, t, J7.2Hz), 2.40 (2H, t,J6.0Hz).

Intermediate 26

9-Phthalimidononan-1-ol

A stirred mixture of 9-bromononanol (Aldrich)(1.0 g, 4.5 mmol),phthalimide potassium derivative (1.85 g, 10 mmol) and DMF (10 ml) washeated at 100° C. for 1 hour. The mixture was allowed to cool to roomtemperature and was partitioned between ethyl acetate and water. Theorganic layer was washed with water, brine, dried over magnesium sulfateand evaporated under reduced pressure to afford the title compound as awhite solid, 1.53 g, quantitative yield. m/z (LCMS ES+, 70 v) 290.1(MH⁺), 312.1 (MNa⁺). δH (CHCl₃-d) 7.81 (2H, m), 7.73 (2H, m), 3.64 (4H,m), 1.68 (2H, m), 1.59 (2H, m), 1.32 (10H, m).Intermediate 27

9-Phthalimidononan-1-a1

To a stirred solution of dimethylsulfoxide (0.568 ml, 8.0 mmol) indichloromethane (50 ml) at −78° was added oxalyl chloride (0.693 ml, 8.0mmol) dropwise. The mixture was stirred at −78° for 15 minutes.Intermediate 26 (2.0 g, 7.0 mmol) in dichloromethane (8 ml) was addedslowly. The mixture was stirred at −78° for 20 minutes. Triethylamine(7.5 ml) was added. The mixture was stirred at −78° for 15 minutes andallowed to warm to room temperature. Water was added; the layers wereseparated and the organic layer was washed with water, brine, dried overmagnesium sulfate and evaporated under reduced pressure to afford thetitle compound as an oil, 2.18 g, quantitative yield. The product had ahigher Rf than the starting material by TLC (1:1 hexane:ethyl acetate;visualised with UV light). δH(CHCl₃-d) 9.68 (1H, s), 7.77 (2H, m), 7.64(2H, m), 3.60 (t, 2H, J=7.5Hz), 2.33 (t, 2H, J=7.4Hz), 1.54 (4H, m),1.25 (8H, m).

Intermediate 28

(8-Carboxyethyl)octyl bromide

To stirred ethanol (100 ml) was added acetyl chloride (10 ml) slowly.The solution was stirred for 30 minutes. 9-Bromononan-1-oic acid (3.50g, 14.8 mmol) (prepared according to the method of. Tranchepain et al,Tetrahedron volume 45, page 2060 (1989)) was added and the resultingsolution heated at reflux for 1 hour. The reaction was observed to becomplete by TLC (1:1 hexane:ethyl acetate; visualised with cericsulphate); the product had a higher Rf than the starting material. Thesolvent was evaporated under reduced pressure to afford the titlecompound (along with a side product thought to be the chloro analog ofthe title compound) as a yellow oil, 3.52 g. δ_(H) (CHCl₃-d) 4.15 (2H,q, J=7.2Hz), 3.42 (2H, t, J=6.8Hz), 2.31 (2H, t, J=7.5Hz), 1.87 (2H, m),1.62 (2H, m), 1.45 (2H, m), 1.34 (8H, m), 1.27 (3H, t, J=7.2Hz).Intermediate 29

(8-Carboxyethyl)octyltriphenylphosphonium bromide

A mixture of the crude Intermediate 28 (3.50 g, 14.8 mmol) andtriphenylphosphine (3.88 g, 14.8 mmol) was heated at 110° for 72 hours.Disappearance of starting material was confirmed by TLC (1:1hexane:ethyl acetate; visualised with ceric sulphate). The reactionmixture was allowed to cool to room temperature and triturated withisopropyl ether to afford the title compound as a yellow oil, 2.25 g,29%. δH(DMSO-d6) 7.90-7.73 (15H, m), 4.04 (2H, q, J=7.1Hz), 3.60 (2H,m), 2.24 (2H, t, J=7.3Hz), 1.50 (4H, m), 1.24 (8H, m), 1.16 (3H, t,J=7.1Hz).Intermediate 30

Z-18-Phthalimidoethyl-9-octadecanoate

To a stirred solution of Intermediate 29 (2.25 g, 4.3 mmol) in anhydroustetrahydrofuran (20 ml) at −78° was added a solution of potassiumbis(trimethylsilyl)amide 0.5M in toluene (8.6 ml, 4.3 mmol) dropwiseover 5 minutes. The solution was allowed to warm to 0°, re-cooled to−78° and a solution of Intermediate 27 (1.20 g, 4.1 mmol) in anhydroustetrahydrofuran (9 ml) was added dropwise over 5 minutes. The mixturewas stirred for 30 minutes at −78°, allowed to warm to room temperatureand stirred for a further 30 minutes before quenching with water (40ml). The organic layer was separated, washed with brine, dried overmagnesium sulfate and evaporated under reduced pressure to afford 2.0 gyellow oil. Chromatography on silica gel; mobile phase 10:1 hexane:ethylacetate loading in toluene gave the title compound as a yellow oil, 380mg, (20%). δ_(H) (C₆H₆-d6) 7.59 (2H, dd, J=3.0, 5.4Hz), 7.00 (2H, dd,J=3.0, 5.4Hz), 5.58 (2H, m), 4.10 (2H, q, J=7.1Hz), 3.65 (2H, t,J=7.3Hz), 2.26 (2H, t, J=7.4Hz), 2.20 (2H, m), 1.70 (2H, m), 1.44 (2H,m), 1.30 (20H, m), 1.10 (3H, t, J=7.1Hz).Intermediate 31

Z-18-Amino-9-octadecenoic acid

Intermediate 30 (100 mg, 0.22 mmol), ethanol (2 ml), water (2 ml) andsodium hydroxide (1.0 g) were heated together at reflux for 48 hours.The reaction was found to have proceeded to completion by TLC(200:20:3:2 dichloromethane:methanol:acetic acid:water; visualizing withninhydrin). The reaction mixture was allowed to cool to roomtemperature, acidified with 2M hydrochloric acid and extracted withethyl acetate. The extract was washed with brine and loaded onto the topof a silica gel column.

Chromatography; mobile phase dichloromethane:methanol:acetic acid:water400:20:3:2 followed by 200:20:3:2 gave the title compound as a whitesolid, 38 mg, (58%). m/z (LCMS ES+, 70 v) 298.0 MH⁺

EXAMPLE 1

NHS-PEG-MAL, MW 2000 (50 mg) purchased from Shearwater was dissolved indistilled water (2 ml) and left overnight. The solution was diluted with0.1M HCl (20 ml) and extracted with DCM (4×25 ml). The combined DCMfractions were then washed with 0.1M HCl (2×20 ml), dried over MgSO₄ andthe solvent removed to give the acid as a waxy white solid, 43 mg, 90%.

m/z (LCMS ES−, 60V) for n=43 2177 ((M-H⁺)⁻).

δ_(H) (CDCl₃) 6.64 (2H, s), 6.37 (1H, br), 3.80-3.64 (4H: 2×m). 3.6-3.3(˜176H, brm), 2.53 (2H, J6.3Hz) 2.45 (2H, t, J7.2Hz).

EXAMPLE 2

A suspension of Intermediate 23 (12 mg, 0.04 mmol) and Et₃N (13 mg,0.133 mmol) in DMF (5 ml) was rapidly heated until a clear solution wasobtained. To the solution was then added NHS-PEG-MAL, MW 3400 (113 mg,0.033 mmol) from Shearwater and the reaction left with no heating for 1hour. MP-Tosic acid resin (0.5 g, 1.43 mmol/g) was added, stirred for 2hours, filtered off and the solvent removed from the filtrate. Theresulting residue was dissolved in 0.1MHCl (20 ml), washed with Et₂O(5×50 ml), extracted into DCM (4×30 ml) and the combined DCM fractionswashed with 0.1M HCl (3×30 ml). The DCM was dried over MgSO₄ and thesolvent removed to yield the product as an off white waxy solid 108 mg,91%.

m/z (LCMS ES−, 60V) for n=73 1890 ((M-2H⁺)²⁻).

δ_(H) (CDCl₃) 6.70 (2H, s), 3.88-3.59 (4H, s), 3.66-3.50 (˜290H, br),3.54 (2H, m), 3.46 (2H, m), 3.42 (2H, t, J4.9Hz), 3.30 (2H, t, J7.1Hz),2.79 (2H, t), 2.53 (2H, t, J7.2Hz), 2.32 (2H, t, J7.5), 1.63 (2H, m),1.55 (2H, m), 1.26 (26H, br).

EXAMPLE 3

Method as for Example 2 except replaced NHS-PEG-MAL, MW 3400 withNHS-PEG-MAL, MW 2000.

m/z (LCMS ES−, 60V) for n=44 2458 ((M-H⁺)⁻).

δ_(H) (CDCl₃) 6.70 (2H, s), 6.53 (2H, br), 3.80-3.42 (˜160H, brm), 3.39(2H, t, J4.9Hz), 3.35 (2H, q, J5.1Hz), 3.15 (2H, q, J6.7Hz), 2.45 (2H,t, J7.2Hz), 2.40 (2H, t, J5.8Hz), 2.24 (2H, t, J5Hz), 1.54 (2H, m), 1.42(2H, m), 1.18 (26H, br).

EXAMPLE 4

Method as for Example 2 except replaced NHS-PEG-MAL, MW 3400 withNektar's new NHS-PEG-MAL, MW 3400 and used DMSO in place of DMF.

m/z (ES) for n=78 1982 ((M-H⁺Cl⁻)²⁻).

δ_(H) (CDCl₃) 6.64 (2H, s), 6.46 (1H, bit), 3.88-3.46 (316H, brm), 3.40(2H, t, J4.9Hz), 3.15 (2H, q, J6.7Hz), 2.40 (2H, t, J5.7Hz), 2.24 (2H,t, J7.5H), 1.56 (2H, p), 1.42 (2H, p), 1.18 (26H, br).

EXAMPLE 5

Method as for Example 2 except replaced Intermediate 23 with 12-aminododecanoic acid.

m/z (LCMS ES−, 60V) for n=74 1848 ((M-2H⁺)²⁻).

δ_(H) (CDCl₃) 6.70 (2H, s), 3.90-3.69 (4H, m), 3.66-3.58 (˜290H, m),3.54 (2H, m), 3.46 (2H, m), 3.42 (2H, t, J4.9Hz), 3.31 (2H, t, J6.7Hz),2.83 (2H, br), 2.54 (2H, t, J7.2Hz), 2.34 (2H, m), 1.63 (2H, m), 1.56(2H, m), 1.28 (14H, br).

EXAMPLE 6

Method as for Example 2 except replaced Intermediate 23 withIntermediate 19 and replaced NHS-PEG-MAL, MW 3400 with NHS-PEG-MAL, MW2000.

m/z (LCMS ES−, 60V) for n=43 2542 ((M-H⁺)⁻).

δ_(H) (CDCl₃) 6.64 (2H, s), 6.54 (1H, br), 6.41 (1H, br), 3.80-3.45(˜160H, br), 3.39 (2H, t, J4.9Hz), 3.35 (2H, q, J5.1Hz), 3.15 (2H, q,J6.7Hz), 2.45 (2H, t, J7.3Hz), 2.41 (2H, t), 2.24 (2H, t, J7.5Hz), 1.55(2H, p, J7.3Hz), 1.42 (2H, m), 1.19 (38H, s).

EXAMPLE 7

Method as for Example 2 except replaced Intermediate 23 withIntermediate 19 and replaced NHS-PEG-MAL, MW 3400 with Intermediate 3and DMSO used in place of DMF.

m/z (LCMS ES+) 567.7 ((MH₂)²⁺).

δ_(H) (CDCl₃) 6.64 (2H, s), 6.68 (1H, brt), 6.63 (2H, s), 6.48 (1H, br),3.77 (2H, t, J7.2Hz), 3.66 (2H, t, J5.7Hz), 3.57 (44H, brs), 3.47 (2H,t, J5.0Hz), 3.35 (2H, q, J4.9Hz), 3.16 (2H, q, J6.6Hz), 2.44 (4H, m),2.25 (2H, t, J7.5Hz), 1.55 (2H, p, J7.4Hz), 1.42 (2H, P, J6.9Hz), 1.18(38H, brs).

EXAMPLE 8

Method as for Example 2 except replaced Intermediate 23 withIntermediate 19 and replaced NHS-PEG-MAL, MW 3400 with Intermediate 13and DMSO used in place of DMF.

m/z (LCMS ES+) 870.3 (MH+).

δ_(H) (CDCl₃) 7.05 (1H, br), 6.98 (1H, br), 6.62 (2H, s), 3.94 (2H, s),3.92 (2H, s), 3.59 (20H, br), 3.47 (2H, t, J7.0Hz), 3.23 (4H, m), 2.25(2H, t, J7.5Hz), 1.56 (4H, m), 1.45 (4H, m), 1.18 (38H, brs).

EXAMPLE 9

Intermediate 7 (124 mg, 0.015 mmol) was dissolved in 9:1 TFA:DCM (3 ml)and the solvent removed after 25 minutes. The residue was dissolved inDCM (3 ml), to this added Et₃N (9 mg, 0.088 mmol) (may need to add moreto obtain a basic solution due to excess TFA) and maleimido propionicacid NHS ester (12 mg, 0.044 mmol). After overnight reaction the solventwas removed, the residue, the residue dissolved in 0.1M HCl (25 ml) andwashed with Et₂O (10×40 ml). The aqueous layer was then extracted intoDCM (3×30 ml), the combined DCM fractions washed with 0.1M HCl (3×30 ml)and the solvent removed to yield the title compound as an off whitesolid 80 mg, 64%.

δ_(H) (CDCl₃) 7.01 (1H, brt), 6.90 (1H, d, J6.9Hz), 6.64 (2H, s), 6.52(1H, t), 4.85 (2H, brt), 4.27 (1H, m), 4.14 (4H, m), 3.78-3.42 (˜640H,brm), 3.39 (2H, m), 3.36 (2H, m), 3.08 (4H, m), 2.48 (2H, t, J7.0Hz),2.23 (4H, m), 2.19 (2H, m), 1.73 (1H, m), 1.69-1.54 (7H, m), 1.41 (4H,m), 1.18 (52H, br).

EXAMPLE 10

Method as for Example 9 except Intermediate 8 was used in place ofIntermediate 7. 189 mg, 75%.

m/Z (ES−) 2751 n=80 ((M-3H⁺)³⁻).

δ_(H) (CDCl₃) 7.20 (1H, brs), 6.95 (1H, br), 6.85 (1H, br), 6.67 (2H,s), 4.84 (2H, br), 4.30 (1H, m), 4.18 (4H, m), 3.85-3.45 (˜640H, br),3.42 (4H, m), 3.10 (4H, m), 2.50 (2H, t), 2.27 (6H, m), 1.75 (1H, m),1.7-1.5 (7H, m), 1.42 (4H, m), 1.20 (76H, br).

EXAMPLE 11

To a solution of Intermediate 25 (70 mg, 0.48 mmol) in DMSO (1.5 ml) wasadded a hot solution of Intermediate 19 (25 mg, 0.057 mmol) and Et₃N (24mg, 0.239 mmol) in DMSO (2.5 ml) (heated with hot air gun untildissolved and immediately used). The reaction was allowed to cool toambient temperature and after 4 hours MP-Tosic acid resin (200 mg, 1.43mmol/g) added. After 1 hour the resin was filtered off, the solventremoved and the residue dissolved in DCM (40 ml). The DCM solution waswashed with 0.1M HCl (5×25 ml), dried over MgSO4 and the solventremoved. The residue was then triturated with 0.1M HCl and the solventremoved to give the desired material 55 mg, 66% as a yellow solid.

m/z (ES+, 70V) 868 ((MH₂)²⁺).

δ_(H) (CDCl₃) 6.68 (1H, br), 6.63 (2H, s), 6.50 (1H, br), 4.00-3.20(102H, brm), 3.15 (2H, q, J6.7Hz), 2.41 (6H, br), 2.24 (2H, t, J7.4Hz),1.55 (2H, p, J7.1Hz), 1.42 (2H, p, J6.9Hz), 1.18 (38H, br).

EXAMPLE 12

Method as for Example 2 except replaced Intermediate 23 withIntermediate 31 and the DMF with DMSO to afford the title compound as awaxy solid.

(LCMS ES+, 70 v) 1882.5 ((MNa₂)²⁺).

δ_(H) (CDCl₃) 6.64 (1H, brs), 6.63 (2H, s), 6.38 (1H, brs), 5.27 (1H,m), 5.27 (1H, m), 3.77 (3H, m), 3.57 (˜320H, m), 3.46 (2H, m), 3.35 (2H,m), 3.16 (2H, m), 2.44 (4H, m), 2.24 (2H, t, J=7.4Hz), 1.94 (4H, m),1.55 (2H, m), 1.42 (2H, m), 1.22 (18H, m).

1. An albumin-binding compound comprising a spacer group, awater-soluble bridging group, a fatty acid chain and an acidic groupwherein the water-soluble bridging group is disposed between the spacergroup and the fatty acid chain, the fatty acid chain is disposed betweenthe water-soluble group and the acidic group, and the acidic group isattached to the distal end of the compound.
 2. An albumin-bindingcompound according to claim 1 to which one or more biologically activemoieties are attached.
 3. An albumin-binding compound according to claim2 selected from a compound of formula (I), (II), (III) and (IV):

wherein: Z, Z¹ and Z² each independently represent the residue of abiologically active moiety; L, L¹ and L² each independently represent aspacer group; Y, Y¹ and Y² each independently represent a covalent bondor —(CH₂)_(y)—; B, B¹ and B² each independently represent a covalentbond, —CONH—, —NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O— or —NHCONH—; V¹and V² each independently represent a covalent bond or —(CH₂)_(v)—; X¹and X² each independently represent CR¹ or N; M¹ represents a covalentbond or —(CH₂)_(m)—; W¹ and W² each independently represent a covalentbond or —(CH₂)_(w)—; A¹ and A² each independently represent —CONH—,—NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O— or —NHCONH—; E, E¹ and E² eachindependently represent a covalent bond or —(CH₂)_(e)—; P, P¹ and P²each independently represent a water-soluble bridging group; T, T¹ andT² each independently represent a covalent bond or a linker group; F, F¹and F² each independently represent a fatty acid chain; Q, Q¹ and Q²each independently represent an acidic group; R¹ represents hydrogen orC₁₋₄ alkyl; R² represents hydrogen or C₁₋₄ alkyl; e is 1, 2, 3 or 4; vis 1, 2, 3 or 4; w is 1, 2, 3 or 4; y is 1, 2, 3, 4, 5 or 6; and m is 1,2 or
 3. 4. An albumin-binding compound according to claim 3 in which F,F¹ and F² are each independently a straight chain of between 11 and 24carbon atoms.
 5. An albumin-binding compound according to claim 4 inwhich F, F¹ and F² are each independently a straight chain of 17 or 23carbon atoms.
 6. An albumin-binding compound according to claim 3 inwhich Z, Z¹ and Z² are each the residue of an antibody or antibodyfragment.
 7. An albumin-binding compound according to claim 3 in whichL, L¹ and L² are each succinimide.
 8. An albumin-binding compoundaccording to claim 3 in which P, P¹ and P² are each polymer moietiescomprising the repeating unit [OCH₂CH₂], where n is between 5 and 100.9. An albumin-binding compound according to claim 3 in which T, T¹ andT² are each independently selected from a covalent bond, —CONH—,OCH₂CONH—, —OCONH—, and —NHCO—.
 10. An albumin-binding compoundaccording to claim 3 in which Q, Q¹ and Q² are each CO₂H.
 11. A compoundof formula (V), (VI), (VII) or (VIII):

wherein L³, L⁴ and L⁵ each independently represent groups capable ofattaching the residue Z, Z¹ and Z² respectively, or capable of beingconverted into such groups; Z, Z¹ and Z² each independently representthe residue of a biologically active moiety; Y, Y¹ and Y² eachindependently represent a covalent bond or —(CH₂)_(y)—; B, B¹ and B²each independently represent a covalent bond, —CONH—, —NHCO—, —CO—,—OC(O)N(R²)—, —N(R²)C(O)O— or —NHCONH—; V¹ and V² each independentlyrepresent a covalent bond or —(CH₂)_(y)—; X¹ and X² each independentlyrepresent CR¹ or N; M¹ represents a covalent bond or —(CH₂)_(m)—; W¹ andW² each independently represent a covalent bond or —(CH₂)_(w)—; A¹ andA² each independently represent —CONH—, —NHCO—, —CO—, —OC(O)N(R)—,—N(R²)C(O)O— or —NHCONH—; E, E¹ and E² each independently represent acovalent bond or —(CH₂)_(e)—; P, P¹ and P² each independently representa water-soluble bridging group; T, T¹ and T² each independentlyrepresent a covalent bond or a linker group; F, F¹ and F² eachindependently represent a fatty acid chain; Q, Q¹ and Q² eachindependently represent an acidic group; R¹ represents hydrogen orC₁₋₄alkyl R² represents hydrogen or C₁₋₄ alkyl e is 1, 2, 3 or 4: v is1, 2, 3 or 4; w is 1, 2, 3 or 4, y is 1, 2, 3, 4, 5 or 6; and m is 1, 2or
 3. 12. A compound according to claim 11 in which L³, L⁴ and L⁵ areeach maleimide derivatives.
 13. A compound according to claim 12selected from a compound of formula (IX), (X), (XI), and (XII):

wherein Y, Y¹ and Y² each independently represent a covalent bond or—(CH₂)_(y)—; B, B¹ and B² each independently represent a covalent bond,—CONH—, —NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O— or —NHCONH—; V¹ and V²each independently represent a covalent-bond or —(CH₂)_(v)—; X¹ and X²each independently represent CR¹ or N; M¹ represents a covalent bond or—(CH₂)_(m)—; W.sup.¹ and W.sup.² each independently represent a covalentbond or —(CH₂)_(w)—; A¹ and A² each independently represent —CONH—,—NHCO—, —CO—, —OC(O)N(R²)—, —N(R²)C(O)O— or —NHCONH—; E, E¹ and E2 eachindependently represent a covalent bond or —(CH₂)_(y)—; P, P¹ and P²each independently represent a water-soluble bridging group; T, T¹ andT² each independently represent a covalent bond or a linker group; F, F¹and F² each independently represent a fatty acid chain; R¹ representshydrogen or C₁₋₄ alkyl; R² represents hydrogen or C₁₋₄ alkyl; e is 1, 2,3 or 4; v is 1, 2, 3 or 4; w is 1, 2, 3 or 4; y is 1, 2, 3, 4, 5 or 6;and mis 1,2 or
 3. 14. A compound according to claim 13 selected from

where n is between 5 and
 100. 15. A pharmaceutical compositioncomprising a compound according to claim 2 in association with one ormore pharmaceutically acceptable carriers, excipients or diluents.